The insulin resistance syndrome (IRS) afflicts approximately 47 million Americans. Its principal components include central obesity, elevated triglycerides, decreased high density lipoprotein cholesterol (HDL-C) levels, fasting hyperglycemia, and/or hypertension. Individuals with the IRS are at significantly increased risk for developing type 2 diabetes mellitus and/or coronary heart disease (CHD). While diet and exercise can improve some manifestations of the IRS, pharmacotherapy is often needed to normalize other components. In recent studies from our laboratory, niacin and fish oil (n-3 fatty acids, FA) used in combination in individuals with the IRS improved the lipid phenotype, but also, unexpectedly, the mealinduced suppression of free fatty acid (FFA) flux (an important indicator of adipose tissue insulin sensitivity). This project will explore the clinical efficacy of combined (and mono-) therapy with n-3 FA and niacin on CHD risk factors, on triglyceride and FFA kinetics and on glucose disposal rates in subjects with the IRS. We will conduct a single, randomized, parallel-arm, placebo-controlled trial. Subjects with the IRS (per the NCEP ATP-itl guidelines) will be randomly allocated to one of four intervention groups after a one-month dual placebo run-in period. The groups will be: n-3 FA (3.4 g/d), crystalline niacin (3 g/d), the combination, or duat placebo. The latter two groups will include 20 subjects each while the two-monotherapy arms will have 10 subjects each. Effects on endpoints will be determined at baseline and after four months of treatment. The CHD risk factors include serum lipids and lipoproteins; lipoprotein(a); subfractions of HDL and of low density tipoproteins; tissue plasminogen activator and plasminogen activator inhibitor-1; and blood pressure. Triglyceride kinetics will be determined by bolus injection of 2H/5-glycerol, and FFA kinetics by isotope dilution using a constant infusion of 3H-palmitate in the fasting state, after a standard mixed meal and during the hyperinsulinemic-euglycemic clamp procedure used to evaluate glucose disposal rates. At the completion of these studies, we expect to have detailed information on the potential therapeutic efficacy and the kinetic mechanisms of action of these two nutritional agents. This should lead to more effective therapy for the dyslipidemia of insulin resistance and ultimately to reduced risk for CHD in this burgeoning patient population.